BEAMS ABSTRACT: Overall Prevalence of childhood asthma has significantly increased in the last decades, and one potential explanation for this upsurge is decreased exposure to protective environmental microbes due to improvements in sanitation and use/overuse of antimicrobial products during pregnancy and early life. In support of this contention, several studies in isolated rural communities have reported lower prevalence of asthma among children of animal farmers more heavily exposed to environmental microbes than among their non-farmer peers. If these observations are applicable to more mainstream US populations is unknown. We recently observed that Mexican American children living in Tucson, Arizona have a prevalence of childhood asthma that is fourfold higher than in Nogales, Mexico. This dramatic difference in rates of asthma suggests that, even in this limited geographic region and among an ancestrally similar population, differential exposures may exist which account for relative protection against asthma in Mexico. Tucson is only 70 miles north of Nogales, Mexico, which is a 200k inhabitant city located just south of the US-Mexico border. Nogales, Mexico lacks public sanitation facilities and poverty rates are very high. In preliminary data, we observed marked differences in microbial communities present in dust, drinking water, and in stools of one-month-old children between the two cities. Based on these findings, we propose the Binational Early Asthma and Microbiome Study (BEAMS). The BEAMS overall goals are: to identify divergent early-life microbial and immune developmental trajectories associated with asthma protection in Nogales, Mexico compared with Tucson, Arizona, and the environmental factors that promote them; to isolate the specific microbes, genes and their products that confer such protection; and to ascertain the mechanisms by which these microbial communities or their products promote asthma protection. To accomplish these goals, BEAMS will have three Projects and four Cores. We will enroll 250 pregnant mother/offspring dyads of Mexican ancestry in each city. We will thoroughly assess environmental microbial exposure, maternal gut microbiota and microbial gene expression, maternal immune markers and meconium microbiome. We will relate these characteristics to child?s fecal microbiome and metabolome in early life, to asthma-related immune markers in the child?s blood, as assessed by mass cytometry analysis and single cell epigenetic and gene expression studies, and to asthma-related clinical phenotypes by age 2 years. We will also assess in mouse models the specific molecular mechanism that explain the protective effects against the development of childhood asthma of specific microbial strains and metabolites present in Nogales, Mexico. We expect BEAMS to offer a better understanding of the early origins of asthma and new asthma prevention strategies applicable to Mexican- Americans, and potentially to all Americans.